Contraction of cardiac and skeletal muscle depends in large part on the amount of calcium released from the intracellular calcium store called the sarcoplasmic reticulum (SR).The regulation of this SR calcium is therefore fundamental to heart and muscle performance, and disturbances in the release of this calcium lead to muscle weakness and heart failure. In addition, calcium signaling is involved in the regulation of gene expression that allows striated muscle to adapt to changes in demand or contractile stress. While a detailed understanding of how calcium is released from the SR exists, little is understood about how the stores are replenished. Reports from several groups, including our own, have demonstrated that both cardiac and skeletal muscles are able to sense store depletion and activate calcium entry from the extracellular space in order to replenish the SR (Store operated calcium entry, SOCE). Our preliminary data demonstrate that the recently identified calcium sensor stromal interaction molecule 1 (STIM1) is expressed and functional in striated muscle. Mice lacking a functional STIM1 molecule in the heart demonstrate impaired cardiac function. We hypothesize that STIM1 is critical regulator of the SOC current necessary for repletion of the intracellular stores and required for contractility and calcium dependent gene expression in striated muscle. We therefore propose the following specific aims: Specific Aim1: To determine in vitro the role of STIM1 in mediating store operated calcium entry in striated muscle cells; Specific Aim 2: To determine in vitro the role of STIM1 in calcium dependent gene expression; Specific Aim 3: To determine in vivo the role of STIM1 in regulating store operated calcium entry in cardiac muscle. PUBLIC HEALTH RELEVANCE: The regulation of intracellular calcium is fundamental to the performance of cardiac and skeletal muscle and disturbances in calcium release lead to skeletal muscle and heart failure. Our preliminary data indicates that the calcium sensor stromal interaction molecule 1 (STIM1) is expressed and functional in cardiac and skeletal myocytes and is a critical regulator of calcium within the myocytes. This proposal seeks to further define the function of STIM1 in cardiac and skeletal muscle cells, and to understand its role in cardiac failure.